Trisubstituted thiophenes that modulate intracellular calcium
View Patent ↗Described herein are compounds of Formula (I): wherein A, J, Z, X, R 1 , and R 4 are defined herein, and pharmaceutical compositions containing such compounds, which modulate the activity of store-operated calcium (SOC) channels. Also described herein are methods of using such SOC channel modulators, alone and in combination with other compounds, for treating diseases or conditions that would benefit from inhibition of SOC channel activity.
1. A compound of Formula (I):
wherein:
A is phenyl or benzofuranyl, wherein phenyl and benzofuranyl are each optionally substituted with at least one R; or A is phenyl substituted with two R groups on adjacent carbon atoms wherein the two R groups and the carbon atoms to which they are attached form a C 4 -C 8 cycloalkyl or C 3 -C 8 heterocycloalkyl;
R is selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 3 , —OCF 3 , —C≡CH, —C≡CR 3 , C 1 -C 6 alkylenealkynyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 6 heterocycloalkyl, phenyl, —NHS(═O) 2 R 3 , S(═O) 2 N(R 4 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 3 , —S(═O) 2 NHC(═O)R 4 , N(R 4 ) 2 , —N(R 4 )C(═O)R 3 , —CO 2 R 4 , —C(═O)R 3 , —OC(═O)R 3 , —C(═O)N(R 4 ) 2 , —SR 3 , —S(═O)R 3 , and —S(═O) 2 R 3 ;
J is a bond, —C(═O), N(R 4 ), ——S, or C 1 -C 6 alkylene, wherein C 1 -C 6 alkylene is optionally substituted with at least one R;
R 1 is CO 2 R 2 ,
wherein R 2 is hydrogen;
Z is O;
X is W-L-phenyl, W-L-B, W-L-D, or D wherein phenyl, B, and D are each optionally substituted with at least one R;
W is NR 2 , O or a bond;
L is methylene, ethylene substituted with at least one R, C 3 -C 6 alkylene, C 2 -C 6 alkynylene, C 1 -C 6 heteroalkylene, C 3 -C 6 cycloalkylene, or C 2 -C 6 heterocycloalkylene, wherein methylene, C 3 -C 6 alkylene, C 2 -C 6 alkynylene, C 1 -C 6 heteroalkylene, C 3 -C 6 cycloalkylene, and C 2 -C 6 heterocycloalkylene is optionally substituted with at least one R;
B is selected from furan, thiophene, pyrrole, pyridine, oxazole, thiazole, imidazole, thiadiazole, isoxazole, isothiazole, pyrazole, pyridazine, pyrimidine, pyrazine, oxadiazole, thiadiazole, triazole, indole, benzoxazole, benzothiazole, benzimidazole, benzoxadiazole, benzothiadiazoie, benzotriazole, pyrazolopyridine, imidazopyridine, pyrrolopyridine, pyrrolopyrimidine, indolizine, purine, furopyridine, thienopyridine, furopyrrole, furofuran, thienofuran, 1,4-dihydropyrrolopyrrole, thienopyrrole, thienothiophene, quinoline, isoquinoline, furopyrazole, thienopyrazole, and 1,6-dihydropyrrolopyrazole;
D is C 3 -C 10 cycloalkyl or C 2 -C 9 heterocycloalkyl;
each R 3 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl;
each R 4 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl; or
a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein R 4 is hydrogen.
3. The compound of claim 2 wherein J is a bond.
4. The compound of claim 3 wherein A is benzofuranyl.
5. The compound of claim 4 wherein benzofuranyl is substituted with one R.
6. The compound of claim 3 wherein A is phenyl.
7. The compound of claim 6 wherein phenyl is substituted with one R.
8. The compound of claim 6 wherein phenyl is substituted with two R.
9. The compound of claim 6 wherein phenyl is substituted with three R.
10. The compound of claim 6 wherein R is selected from F, Cl, Br, I, or C 1 -C 6 alkyl.
11. The compound of claim 6 wherein X is W-L-B, and B is selected from benzoxazole, benzothiazole, benzimidazole, pyrazolopyridine, imidazopyridine, benzoxadiazole, benzothiadiazole, and benzotriazole wherein B is optionally substituted with at least one R.
12. The compound of claim 11 wherein B is benzoxazole.
13. The compound of claim 11 wherein B is benzothiazole.
14. The compound of claim 11 wherein B is pyrazolopyridine.
15. The compound of claim 11 wherein B is benzothiadiazole.
16. The compound of claim 11 wherein R is selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 3 , —OCF 3 , —C≡CH, —C≡CR 3 , C 1 -C 6 alkylenealkynyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 6 heterocycloalkyl, and phenyl.
17. The compound of claim 16 wherein R is selected from F, Cl, Br, and I.
18. The compound of claim 1 wherein X is W-L-phenyl where phenyl is optionally substituted with at least one R.
19. The compound of claim 18 wherein R is selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 3 , —OCF 3 , —C≡CH, —C≡CR 3 , C 1 -C 6 alkylenealkyne, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 6 heterocycloalkyl, and phenyl.
20. The compound of claim 18 wherein R is selected from F, Cl, Br, and I.
21. The compound of claim 1 , wherein
L is methylene, ethylene substituted with at least one R, C 3 -C 6 alkylene, C 1 -C 6 heteroalkylene, or C 3 -C 6 cycloalkylene, wherein C 3 -C 6 alkylene, C 1 -C 6 heteroalkylene, and C 3 -C 6 cycloalkylene, is optionally substituted with at least one R.
22. The compound of claim 1 , wherein L is methylene, or ethylene substituted with at least one R.
23. The compound of claim 1 , wherein L is C 3 -C 6 cycloalkylene, wherein C 3 -C 6 cycloalkylene is optionally substituted with at least one R.
24. The compound of claim 1 , wherein L is C 1 -C 6 heteroalkylene, wherein C 1 -C 6 heteroalkylene is optionally substituted with at least one R.
25. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent, excipient, carrier or binder thereof.